Prmt5-Foxm1 Axis Activates Pyrimidine Metabolism In Olk And Oscc

Observe the specific regulatory role of PRMT5 in pyrimidine metabolism in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC) The impact of targeted PRMT5 inhibition on DOK cells was assessed through functional assays. The influence of PRMT5 inhibition on metabolic processes was corroborated using RNA-seq and non-targeted metabolomics, and further validated by qPCR, Western blotting (WB), and targeted metabolomics. To elucidate the downstream mechanisms, WB, ChIP-qPCR, and dual-luciferase reporter assays were employed. The relationship and interaction between PRMT5 and FOXM1 were investigated using subcutaneous xenograft model, as well as OLK and OSCC clinical specimens. Finally, phenotypic and metabolic rescue experiments were conducted to elucidate the underlying mechanisms. Targeted inhibition of PRMT5 markedly reduced the proliferation, migration, and invasion of DOK cells. RNA-seq and metabolomics results showed that targeting PRMT5 significantly inhibited pyrimidine metabolism. The mechanism observed in both DOK and OSCC cell lines is that PRMT5 promotes the activation of the transcription factor FOXM1 through H3R2me2s-K4me3, and collaborates with FOXM1 to enhance the expression of TK1, RRM2, TYMS, and CAD, thereby activating the pyrimidine metabolic pathway. Animal experiments corroborate that the inhibition of PRMT5 and FOXM1 suppresses the proliferation of OSCC tumors. Furthermore, supplementing exogenous dNTPs can partially mitigate the suppression of proliferation, invasion, and migration caused by targeting PRMT5. Consequently, our study suggests that PRMT5 augments pyrimidine metabolism through the epigenetic activation of FOXM1. Targeted interventions against PRMT5 or FOXM1 are considered promising therapeutic strategies for the treatment of OLK and OSCC.